Regulation of transcription activation during cellular development, division and death are tightly regulated in response to intracellular and environmental cues by intricate protein complexes. Such regulation is well represented by the xenobiotic and hypoxia response pathways, where heterodimeric Per-ARNT-SIM (PAS) domain containing transcription factors respond to environmental stress through alterations in protein:protein interactions. In particular, the Aryl hydrocarbon Receptor (AhR) is activated by diverse exogenous and endogenous compounds to induce a conformational response that gates protein recognition. Despite extensive toxicological and cell biological studies of AhR, due to its role in the development and progression of cancer, atherosclerosis, chloracne and sexual development, structural information demonstrating the mechanisms of protein:protein recognition and specificity depending on ligand identity remain largely unknown. Moreover, discerning the role of AhR in human diseases is complicated by seemingly contradictory reports due to cell and tissue type dependent functions and substantial crosstalk with alternative signaling pathways (i.e. estrogen receptor, inflammation response, endocrine system). Structural characterization of AhR activation in response to diverse ligands will aid in delineating direct effects of AhR from indirect effects due to alternative pathway excitation. Of primary importance is determining the conformational landscape induced by AhR agonists and antagonists, and how different ligands direct alternative protein:protein interactions. A molecular understanding of ligand-induced conformational dynamics and subsequent protein recognition can be well characterized using a combination of NMR and X-ray crystallography. PUBLIC HEALTH RELEVANCE: A detailed understanding of ligand-induced conformational states and their role in protein:protein interactions will aid in directing AhR activation and gene regulation. Further, identification of new AhR ligands that select for discrete modes of AhR activation will be of direct therapeutic use in the treatment of cancer.